Methods, systems, and computer program products for detecting pipette tip integrity

ABSTRACT

This invention relates to methods, systems, and computer program products for detecting pipette tip integrity.

RELATED APPLICATION INFORMATION

This application is a continuation of U.S. patent application Ser. No.14/826,749, filed Aug. 14, 2015, which claims the benefit of andpriority to U.S. Provisional Application Ser. No. 62/037,659, filed Aug.15, 2014, U.S. Provisional Application Ser. No. 62/037,650, filed Aug.15, 2014, U.S. Provisional Application Ser. No. 62/037,652, filed Aug.15, 2014, and U.S. Provisional Application Ser. No. 62/037,661, filedAug. 15, 2014, the disclosures of which are hereby incorporated byreference herein in their entirety.

FIELD OF THE INVENTION

This invention relates to methods, systems, and computer programproducts, particularly to methods, systems, and computer programproducts for detecting pipette tip integrity.

BACKGROUND

The isolation of individual colonies of micro-organisms, particularlybacteria, is an important procedure in microbiological laboratories.Traditionally, the isolation of bacteria has been performed manually byskilled laboratory technicians who first dispense a microbiologicalsample onto the surface of a solid growth culture medium, such as agarin a Petri dish, followed by the use of a hand-tool to spread the sampleacross the surface of the medium, known as “streaking”. However, theselaboratory procedures can also be automated.

For both traditional, manual laboratory procedures and automatedlaboratory procedures, monitoring and/or verifying that a sample volumehas been correctly dispensed onto a solid growth culture medium can beimportant. This is because if a sample has not been correctly dispensed,then it can create the risk of a false negative.

BRIEF SUMMARY

It is noted that aspects described with respect to one embodiment may beincorporated in different embodiments although not specificallydescribed relative thereto. That is, all embodiments and/or features ofany embodiments can be combined in any way and/or combination. Moreover,other systems, articles of manufacture, methods, and/or computer programproducts according to embodiments will be or become apparent to one withskill in the art upon review of the following drawings and detaileddescription. It is intended that all such additional systems, articlesof manufacture, methods, and/or computer program products be includedwithin this description, be within the scope of the present inventiveconcept, and be protected by the accompanying claims.

Some embodiments are directed to systems, articles of manufacture,methods and/or computer program products for detecting pipette tipintegrity. In some embodiments, operations include collecting pressuredata while aspirating a gas into a pipette tip attached to a pipette. Insome embodiments, the pipette tip includes a filter. In someembodiments, the pressure data includes a plurality of pressure valuesmeasured at an internal portion of the pipette and taken over a giventime interval. In some embodiments, the plurality of pressure valuesinclude a maximum pressure value and a minimum pressure value.

Some embodiments include estimating a pressure range value between themaximum pressure value and the minimum pressure value. In someembodiments, responsive to the pressure range value being greater thanor equal to a lower threshold and the pressure range value being lessthan or equal to an upper threshold, it is determined that the pipettetip attached to the pipette is properly functioning. Some embodimentsinclude, responsive to the pressure range value being less than a lowerthreshold. In some embodiments, responsive to the pressure range valuebeing greater than an upper threshold, it is determined that the pipettetip attached to the pipette is not properly functioning.

In some embodiments, collecting pressure data while aspirating gas intothe pipette tip attached to the pipette includes measuring pipettepressure at given time intervals. Some embodiments include aspiratinggas into the pipette tip attached to the pipette over a given timeinterval.

In some embodiments, collecting pressure data while aspirating gas intothe pipette tip attached to the pipette includes aspirating the gas at agiven rate of aspiration. Some embodiments include aspirating gas a rateof aspiration in a range of about 300 μL/s to about 700 μL/s.

In some embodiments, collecting pressure data while aspirating gas intothe pipette tip attached to the pipette includes aspirating gas into thepipette tip prior to aspirating a liquid into the pipette tip. Someembodiments include collecting pressure data while aspirating a givenvolume of gas into the pipette tip attached to the pipette.

In some embodiments, estimating the pressure range value between themaximum pressure value and the minimum pressure value includessubtracting the minimum pressure value from the maximum pressure valueto obtain the pressure range value.

Some embodiments include that the upper threshold and/or the lowerthreshold is/are determined using a given rate of aspiration. In someembodiments, the given rate of aspiration is in a range of about 300μL/sec to about 700 μL/sec. Some embodiments include that the given rateof aspiration is the same as the rate of aspiration for aspirating thegas into the pipette tip attached to the pipette.

Some embodiments include, responsive to the pressure range value beinggreater than or equal to the lower threshold and the pressure rangevalue being less than or equal to the upper threshold, determining thatthe pipette tip attached to the pipette is suitable for use.

Some embodiments include, responsive to the pressure range value beinggreater than or equal to the lower threshold and the pressure rangevalue being less than or equal to the upper threshold, aspirating aliquid into the pipette tip.

Some embodiments include, responsive to the pressure range value beingless than the lower threshold or the pressure range value being greaterthan the upper threshold, removing the pipette tip from the pipette.

Some embodiments include, responsive to the pressure range value beingless than the lower threshold or the pressure range value being greaterthan the upper threshold, determining that the pipette tip is defective,clogged, and/or improperly attached to the pipette.

Some embodiments include, detecting that the pipette tip is defective orwithout a filter responsive to the pressure range value being less thanthe lower threshold.

Some embodiments include, detecting that the pipette tip is defectiveresponsive to the pressure range value being greater than the upperthreshold. In some embodiments, the pipette tip is a clogged.

In some embodiments, the maximum pressure value is measured at a firstpoint in time and the minimum pressure value is measured at a secondpoint in time and the first point in time is before the second point intime. In some embodiments, the maximum pressure value is measured at afirst point in time and the minimum pressure value is measured at asecond point in time and the second point in time is before the firstpoint in time.

Some embodiments are directed to systems, articles of manufacture,methods and/or computer program products for positioning a pipetteand/or detecting a surface using a pipette. In some embodiments,operations include positioning a pipette at a first distance above asurface using a first position detector and positioning the pipette at asecond distance above the surface using a second position detector thatis different from the first position detector, wherein the seconddistance is less than the first distance. In some embodiments, thesecond position detector includes a pipette pressure detector and thefirst position detector uses a metric other than pressure. Someembodiments include, prior to positioning the pipette at the seconddistance, contacting the surface with a tip of the pipette.

In some embodiments, operations include measuring a pipette pressure atan internal portion of a pipette to generate a plurality of pipettepressure values. Some embodiments include determining a pressuredifference relative to at least one previously measured pipette pressurevalue. Some embodiments include estimating at least one statisticalvariable corresponding to a rate of change in pipette pressure. In someembodiments, the at least one statistical variable is compared to atleast one pipette pressure related threshold. Some embodiments include,responsive to comparing the at least one statistical variable to the atleast one pipette pressure related threshold, estimating a pipetteposition. Some embodiments include, responsive to comparing the at leastone statistical variable to the at least one pressure related threshold,determining if the surface has been contacted with the pipette tip.

In some embodiments, measuring the pipette pressure includes measuringthe pipette pressure with a liquid and/or gas in a pipette tip attachedto the pipette. In some embodiments, measuring the pipette pressureincludes measuring the pipette pressure at given time intervals. Someembodiments include measuring the pipette pressure while aspirating gasinto a pipette tip attached to the pipette and while the pipette ismoving toward a surface and/or the surface is/are moving toward thepipette. In some embodiments, the pipette is moving downward in az-direction toward the surface. Some embodiments include the pipetteaspirating gas at a constant flow rate.

Some embodiments include, prior to estimating the at least onestatistical variable, estimating the rate of change in pipette pressure.In some embodiments, estimating the rate of change in pipette pressureincludes mathematically weighting the pressure difference to provide aweighted pressure difference. In some embodiments, estimating the rateof change in pipette pressure includes summing the weighted pressuredifference with at least one weighted previously calculated rate ofchange in pipette pressure. In some embodiments, the pressure differenceis weighted by about 0% to 49% and the previously calculated rate ofchange in pipette pressure is weighted by about 51% to about 100%.

In some embodiments, estimating the at least one statistical variableincludes estimating an average rate of change in pipette pressure. Insome embodiments, estimating the at least one statistical variableincludes estimating a ratio relating to the rate of change in pipettepressure. In some embodiments, the ratio relating to the rate of changein pipette pressure includes the rate of change in pipette pressure andthe average rate of change in pipette pressure.

In some embodiments, comparing the at least one statistical variableincludes comparing the rate of change in pipette pressure to a firstpressure related threshold and comparing a statistical variable to asecond pressure related threshold. In some embodiments, the at least onepressure related threshold is determined using a given rate ofaspiration and/or a given rate of movement. In some embodiments, thestatistical variable is a ratio of the rate of change in pipettepressure divided by an average rate of change in pipette pressure. Insome embodiments, the first pressure related threshold is a rate ofchange in pipette pressure threshold and the second pressure relatedthreshold is a pipette pressure ratio threshold. Some embodimentsinclude detecting contact with a surface detected when the rate ofchange in pipette pressure is less than or equal to the rate of changein pipette pressure threshold and the ratio of the rate change inpipette pressure divided by the average rate of change in pipettepressure is greater than or equal to the pipette pressure ratiothreshold.

In some embodiments, estimating the pipette position includes estimatingthe position of a pipette tip relative to a surface. In someembodiments, estimating the pipette position includes determining that asurface is not in contact with the pipette and, responsive todetermining that the surface is not in contact with the pipette,continuing to estimate the pipette position. In some embodiments,estimating the pipette position includes determining that a surface isin contact with the pipette. In some embodiments, determining if thesurface has been contacted with the pipette tip includes estimating theposition of the pipette tip relative to the surface.

Some embodiments include determining that the surface is in contact withthe pipette by determining that the distal orifice of a pipette tipattached to the pipette has sealed with the surface. In someembodiments, determining that the surface is in contact with the pipetteincludes detecting at least two consecutive data points that indicatecontact to the surface with the pipette.

Some embodiments include, responsive to determining that the surface isin contact with the pipette, stopping movement of the pipette toward thesurface and adjusting the pipette to a position above the surface. Insome embodiments, responsive to determining that the surface is incontact with the pipette, stopping movement of the surface toward thepipette and adjusting the surface to a position below the pipette. Someembodiments include, responsive to determining that the surface is incontact with the pipette, stopping the aspiration of gas.

In some embodiments, operations include aspirating a liquid into thepipette tip and positioning the pipette tip at a first distance above asurface. Some embodiments include moving the pipette toward the surfacewhile aspirating gas into the pipette tip. Some embodiments includemeasuring pipette pressure at an internal portion of the pipette andcollecting pipette pressure data. In some embodiments, measuring pipettepressure at an internal portion of the pipette includes generating aplurality of pipette pressure values. In some embodiments, the pipettepressure data includes the plurality of pipette pressure values. In someembodiments, contact to the surface with the pipette tip is detectedusing the pipette pressure data.

Some embodiments are directed to systems, articles of manufacture,methods and/or computer program products for verifying dispensing of afluid from a pipette. In some embodiments, operations include collectingpressure data while dispensing fluid from a pipette tip attached to apipette. In some embodiments, the pressure data includes a plurality ofpressure values measured at an internal portion of the pipette and takenover a given time interval. In some embodiments, the plurality ofpressure values includes a maximum pressure value and a minimum pressurevalue. Some embodiments include estimating a pressure range valuebetween the maximum pressure value and the minimum pressure value. Someembodiments include determining that the fluid included a liquid,responsive to the pressure range value being greater than or equal to atleast one threshold. Some embodiments include determining that the fluiddid not include a liquid, responsive to the pressure range value beingless than the at least one threshold.

In some embodiments, collecting pressure data while dispensing fluidfrom the pipette tip attached to the pipette includes measuring pipettepressure at given sampling time intervals. Some embodiments includedispensing fluid from the pipette tip attached to the pipette over thegiven time interval.

In some embodiments, collecting pressure data while dispensing fluidfrom the pipette tip attached to the pipette includes dispensing thefluid at a given rate. In some embodiments, the given rate is in a rangeof about 5 μL/sec to about 400 μL/sec.

Some embodiments include, prior to collecting pressure data whiledispensing fluid from the pipette tip attached to the pipette,aspirating a gas into the pipette tip and subsequently aspirating aliquid into the pipette tip. In some embodiments, prior to collectingpressure data while dispensing fluid from the pipette tip attached tothe pipette, at least a portion of the liquid is dispensed from thepipette tip.

In some embodiments, collecting pressure data while dispensing fluidfrom the pipette tip attached to the pipette includes dispensing allfluid present in the pipette tip in the given time interval.

In some embodiments, estimating the pressure range value between themaximum pressure value and the minimum pressure value includessubtracting the minimum pressure value from the maximum pressure valueto obtain the pressure range value.

Some embodiments include prior to estimating the pressure range valuebetween the maximum pressure value and the minimum pressure value,removing a portion of pressure values from the plurality of pressurevalues. In some embodiments, the portion of pressure values are a givennumber of consecutive pressure values. In some embodiments, the portionof pressure values includes the initial pressure value in the pluralityof pressure values.

In some embodiments, determining that the fluid did not include a liquidindicates that a dispensing error occurred.

Some embodiments include estimating a pressure area ratio thatidentifies at least two pressure data curves, each of the at least twopressure data curves corresponding to at least a portion of theplurality of pressure values. In some embodiments, the pressure arearatio is compared to at least one threshold. Some embodiments includedetermining that the fluid included a sufficient amount of the liquid,responsive to the pressure area ratio being greater than at least onethreshold. Some embodiments include determining that the fluid did notinclude a sufficient amount of the liquid, responsive to the pressurearea ratio being less than or equal to at least one threshold.

In some embodiments, estimating the pressure area ratio includesestimating a maximum area corresponding to a pressure data curve thatcorresponds to the maximum pressure value and the minimum pressurevalue. In some embodiments, estimating the pressure area ratio includesestimating an actual pressure area corresponding to a pressure datacurve that corresponds to the plurality of pressure values. Someembodiments include multiplying the pressure range value by the giventime interval to estimate the maximum area. In some embodiments, thegiven time interval is the number of pressure values in the plurality ofpressure values multiplied by the given sampling time interval betweenconsecutive pressure values in the plurality of pressure values.

In some embodiments, estimating the actual pressure area includessumming areas of a plurality of rectangles. In some embodiments, a widthof each rectangle of the plurality of rectangles is the given samplingtime interval between consecutive pressure values in the plurality ofpressure values. In some embodiments, a height of each rectangle of theplurality of rectangles is a midpoint between at least two consecutivepressure values minus the minimum pressure value.

In some embodiments, determining that the fluid did not include asufficient amount of the liquid indicates that a dispensing erroroccurred.

Some embodiments are directed to systems, articles of manufacture,methods and/or computer program products for detecting a droplet. Insome embodiments, operations include estimating a plurality of rate ofchange in pipette pressure values during a given time interval. Someembodiments include detecting the formation of a droplet at a distal endof a pipette tip attached to a pipette, responsive to at least one ofthe plurality of rate of change in pipette pressure values being greaterthan or equal to an upper pressure related threshold and at least one ofthe plurality of rate of change in pipette pressure values being lessthan or equal to a lower pressure related threshold.

In some embodiments, estimating the plurality of rate of change inpipette pressure values during the given time interval includesmeasuring a pipette pressure at an internal portion of a pipette atgiven sampling time intervals to generate a plurality of pipettepressure values. In some embodiments, estimating the plurality of rateof change in pipette pressure values during the given time intervalincludes determining a plurality of pressure differences relative to atleast one previously measured pipette pressure value. In someembodiments, estimating the plurality of rate of change in pipettepressure values during the given time interval includes mathematicallyweighting each of the plurality of pressure differences to provide theplurality of rate of change in pipette pressure values.

In some embodiments, mathematically weighting each of the plurality ofpressure differences to provide the plurality of rate of change inpipette pressure values includes weighting a most recently determinedpressure difference to provide a weighted pressure difference. In someembodiments, mathematically weighting each of the plurality of pressuredifferences to provide the plurality of rate of change in pipettepressure values includes weighting at least one previously calculatedrate of change in pipette pressure value to provide a weightedpreviously calculated rate of change in pipette pressure value. Someembodiments include summing the weighted pressure difference and theweighted previously calculated rate of change in pipette pressure value.In some embodiments, the most recently determined pressure difference isweighted by about 0% to 49% and the at least one previously calculatedrate of change in pipette pressure value is weighted by about 51% toabout 100%.

In some embodiments, the plurality of rate of change in pipette pressurevalues changes over a period of time.

Some embodiments include determining the upper pressure relatedthreshold and/or the lower pressure related threshold using a given rateof dispense.

In some embodiments, the droplet has a volume in a range of about 0.5 μLto about 3.5 μL.

In some embodiments, at least one of the plurality of rate of change inpipette pressure values corresponds to a rate of change in pipettepressure while the pipette is dispensing a gas. In some embodiments, atleast one of the plurality of rate of change in pipette pressure valuescorresponds to a rate of change in pipette pressure while the pipette isdispensing a liquid.

Some embodiments include, responsive to detecting the formation of thedroplet, stopping dispensing of liquid from the pipette tip.

In some embodiments, a clog is detected in the pipette tip attached tothe pipette. In some embodiments, detecting the clog in the pipette tipattached to the pipette includes determining that a given number of rateof change in pipette pressure values of the plurality of rate of changein pipette pressure values are greater than or equal to a first clogrelated threshold. In some embodiments, detecting the clog in thepipette tip attached to the pipette includes determining that an updatedpressure difference corresponding to a most recently measured pipettepressure value of the plurality of pipette pressure values is greaterthan a second clog related threshold.

In some embodiments, the given number of rate of change in pipettepressure values of the plurality of rate of change in pipette pressurevalues corresponds to a given period of time.

Some embodiments include estimating the updated pressure difference. Insome embodiments, estimating the updated pressure difference includesselecting a minimum pipette pressure value from the plurality of pipettepressure values and subtracting the minimum pipette pressure value fromthe most recently measured pipette pressure value of the plurality ofpipette pressure values.

In some embodiments, the second clog related threshold corresponds to acumulative rise in pressure of a given value. Some embodiments includedetermining the first clog related threshold and/or the second clogrelated threshold using a given rate of dispense.

Some embodiments include detecting that the pipette tip does not containa liquid. In some embodiments, detecting that the pipette tip does notcontain the liquid includes estimating a plurality of changes inpressure over a given period of time. In some embodiments, detectingthat the pipette tip does not contain the liquid further includesdetermining that a portion of the plurality of changes in pressureindicate no significant change in pressure. In some embodiments, theportion of the plurality of changes in pressure that indicates nosignificant change in pressure is at least 50%.

In some embodiments, estimating the plurality of changes in pressureover the given period of time includes measuring the pipette pressure atan initial point in time and estimating the plurality of changes inpressure at a given point in time after the initial point in time.

Some embodiments include measuring a pipette pressure at an internalportion of the pipette including a pipette tip attached thereto togenerate a plurality of pipette pressure values. In some embodiments, apressure difference relative to at least one previously measured pipettepressure value is determined. Some embodiments include providing aplurality of pressure difference values. In some embodiments, a portionof the plurality of pressure difference values is compared with an upperpressure related threshold and a lower pressure related threshold. Someembodiments include detecting the formation of a droplet, responsive todetermining that at least one pressure difference value of the portionof the plurality of pressure difference values is greater than or equalto the upper pressure related threshold and that at least one pressuredifference value of the portion of the plurality of pressure differencevalues is less than or equal to the lower pressure related threshold.

In some embodiments, comparing the portion of the plurality of pressuredifference values with the upper pressure related threshold and thelower pressure related threshold includes comparing a portion of aplurality of rate of change in pipette pressure values with the upperpressure related threshold and the lower pressure related threshold.

Some embodiments include estimating a rate of change in pipette pressureand providing a plurality of rate of change in pipette pressure values.In some embodiments, estimating the rate of change in pipette pressureincludes mathematically weighting the pressure difference to provide aweighted pressure difference. In some embodiments, estimating the rateof change in pipette pressure includes summing the weighted pressuredifference with at least one weighted previously calculated rate ofchange in pipette pressure. In some embodiments, the pressure differenceis weighted by about 0% to 49% and the previously calculated rate ofchange in pipette pressure is weighted by about 51% to about 100%.

Some embodiments include measuring the pipette pressure at givensampling time intervals. In some embodiments, measuring the pipettepressure includes measuring the pipette pressure while the pipette ispositioned at a given position.

In some embodiments, comparing the portion of the plurality of pressuredifference values with the upper pressure related threshold and thelower pressure related threshold includes comparing at least twopressure difference values.

In some embodiments, the plurality of pressure difference values changesover a period of time.

Some embodiments include determining the upper pressure relatedthreshold and/or the lower pressure related threshold using a given rateof dispense.

In some embodiments, the droplet has a volume in a range of about 0.5 μLto about 3.5 μL.

In some embodiments, at least one pressure difference value of theportion of the plurality of pressure difference values corresponds to apipette pressure while the pipette is dispensing a gas. In someembodiments, at least one pressure difference value of the portion ofthe plurality of pressure difference values corresponds to a pipettepressure while the pipette is dispensing a liquid.

Some embodiments include, responsive to detecting the formation of thedroplet, stopping dispensing of liquid from the pipette tip.

Some embodiments include detecting a clog in the pipette tip attached tothe pipette. In some embodiments, detecting the clog in the pipette tipattached to the pipette includes determining that a given number of rateof change in pipette pressure values of the plurality of rate of changein pipette pressure values are greater than or equal to a first clogrelated threshold. In some embodiments, detecting the clog in thepipette tip attached to the pipette includes determining that an updatedpressure difference corresponding to a most recently measured pipettepressure value of the plurality of pipette pressure values is greaterthan a second clog related threshold.

In some embodiments, the given number of rate of change in pipettepressure values of the plurality of rate of change in pipette pressurevalues corresponds to a given period of time.

Some embodiments include estimating the updated pressure difference. Insome embodiments, estimating the updated pressure difference includesselecting a minimum pipette pressure value from the plurality of pipettepressure values and subtracting the minimum pipette pressure value fromthe most recently measured pipette pressure value of the plurality ofpipette pressure values.

In some embodiments, the second clog related threshold corresponds to acumulative rise in pressure of a given value. In some embodiments, thefirst clog related threshold and/or the second clog related thresholdis/are determined using a given rate of dispense.

Some embodiments include detecting that the pipette tip does not containa liquid. In some embodiments, detecting that the pipette tip does notcontain a liquid includes estimating a plurality of changes in pressureover a given period of time. In some embodiments, detecting that thepipette tip does not contain the liquid includes determining that aportion of the plurality of changes in pressure indicate no significantchange in pressure. In some embodiments, the portion of the plurality ofchanges in pressure that indicates no significant change in pressure isat least 50%.

In some embodiments, estimating the plurality of changes in pressureover the given period of time includes measuring the pipette pressure atan initial point in time and estimating the plurality of changes inpressure at a given point in time after the initial point in time.

In some embodiments, determining the pressure difference relative to theat least one previously measured pipette pressure includes measuring thepipette pressure at an initial point in time and determining thepressure difference relative to the least one previously measuredpipette pressure at a given point in time after the initial point intime. Some embodiments include that the given point in time after theinitial point in time corresponds to a volume of gas present in thedistal portion of the pipette tip at the initial point in time.

Some embodiments of the present disclosure are directed to computerprogram products that include a computer readable storage medium havingcomputer readable program code embodied in the medium. The computer codemay include computer readable code to perform any of the operations asdescribed herein.

Some embodiments of the present disclosure are directed to a computersystem that includes at least one processor and at least one memorycoupled to the processor. The at least one memory may include computerreadable program code embodied therein that, when executed by the atleast one processor causes the at least one processor to perform any ofthe operations as described herein.

It is noted that aspects of the disclosure described with respect to oneembodiment, may be incorporated in a different embodiment although notspecifically described relative thereto. That is, all embodiments and/orfeatures of any embodiment can be combined in any way and/orcombination. These and other objects and/or aspects of the presentinventive concept are explained in detail in the specification set forthbelow.

BRIEF DESCRIPTION OF THE DRAWINGS

Aspects of the present disclosure are illustrated by way of example andare not limited by the accompanying figures with like referencesindicating like elements.

FIG. 1 is a perspective view from the front of an automated streakingapparatus according to some embodiments of the present inventive subjectmatter.

FIG. 2 is a perspective view from the rear of the apparatus of FIG. 1according to some embodiments of the present inventive subject matter.

FIG. 3 is a perspective view from above a part of the apparatus of FIG.1 according to some embodiments of the present inventive subject matter.

FIG. 4 is a perspective view of a pipette pressure detector according tosome embodiments of the present inventive subject matter.

FIG. 5 is a flowchart illustrating operations in methods according tosome embodiments of the present inventive subject matter.

FIG. 6 is a flowchart illustrating operations in systems according tosome embodiments of the present inventive subject matter.

FIG. 7 is a flowchart illustrating operations in systems according tosome embodiments of the present inventive subject matter.

FIG. 8 is a block diagram illustrating systems according to someembodiments of the present inventive subject matter.

DETAILED DESCRIPTION

As discussed herein, systems, articles of manufacture, methods, and/orcomputer program products of the present inventive subject matter mayprovide an effective and efficient way to detect pipette tip integrity.Some embodiments of the present inventive subject matter may provide theability to monitor and/or verify that a liquid sample volume iscorrectly dispensed onto a surface of a target, such as a surface ofsolid growth culture medium (e.g., agar). Thus, some embodiments of thepresent inventive subject matter may reduce the risk of a falsenegative. For example, if a pipette tip is not functioning properly(e.g., there is a clog or leak in the pipette tip or the pipette tip isnot installed or attached properly), then no or an insufficient amountof a liquid sample may be dispensed onto a surface, such as a surface ofsolid growth culture medium (e.g., agar). This may result in a falsenegative if the condition is not detected. Some embodiments of thepresent inventive subject matter may provide the ability to detectand/or determine the integrity of a pipette tip and/or if a pipette tipis functioning properly. In some embodiments, it may be determined if apipette tip is suitable for use or is not suitable for use. In someembodiments, determining that a pipette tip is suitable for use includesdetermining that that a pipette tip attached to a pipette is suitable toaspirate and dispense a liquid. Some embodiments include, responsive todetermining that a pipette tip is functioning properly and/or suitablefor use, aspirating a liquid into the pipette tip. “Liquid” as usedherein refers to a sample having a viscosity suitable for aspirating anddispensing using a pipette, but which may include solid particles. Insome embodiments, the liquid sample is a biological sample.

In some embodiments, systems, articles of manufacture, methods, and/orcomputer program products of the present inventive subject matter may beused with and/or in an automated apparatus. The automated apparatus maybe an apparatus for positioning a pipette and/or for pipetting a liquidonto a surface of a target, such a surface of solid growth culturemedium (e.g., agar). In some embodiments, the automated apparatus may bean apparatus for inoculating and streaking a solid growth culture mediumin a plate, such as, for example, the apparatus illustrated in FIGS. 1and 2.

Reference is now made to FIGS. 1 and 2, which are a perspective viewfrom the front and rear, respectively, of an automated streakingapparatus according to some embodiments of the present inventive subjectmatter. The apparatus includes a plate supply (indicated by the letterA) that includes a plurality of input plate cassettes 10 (only cassettes10 a and 10 f are shown) supported on an upper frame (not shown) for thesupply of raw plates to the apparatus, together with a plate store(indicated by the letter B) that includes a plurality of output platecassettes 11 (only cassettes 11 a and 11 f are shown) also supported onthe upper frame for the storage of processed plates from the apparatus.Also shown in FIG. 1 is an inoculation and streaking station (indicatedby the letter C).

In some embodiments, the plate supply A and the plate store B aresupported by the upper frame so as to be in front of a main gantry 12,along which various of operative carriages of the apparatus may move, aswill be explained below. The various parts of the inoculation andstreaking station C may be supported by a lower frame (not shown).

Operatively engaged for sliding movement along the main gantry 12 is aplate supply carriage 14 a and a plate store carriage 14 b, which form apart of a plate transfer feed mechanism and a plate transfer storemechanism, respectively. These carriages are both configured formovement along the main gantry 12 (in the x direction) to move a plate(16 a or 16 b) from the plate supply A to the inoculation and streakingstation C and then to the plate store B. The carriages 14 a, 14 b arealso configured to provide movement of a plate 16 a, 16 b along verticalguiderails 18 a, 18 b thereon to raise and/or lower such plate 16 a, 16b in the z direction to or from the respective cassettes 10 a to 10 f,and 11 a to 11 f and to or from either or both of the dual plateorientation mechanisms 20 a, 20 b.

In this respect, it can be seen that each of the carriages 14 a, 14 bincludes a plate support tray 22 a, 22 b upon which the plates 16 a, 16b rest in transit, the plate support trays 22 a, 22 b being suitablymounted to their respective carriages for the movement described above.In some embodiments, the plates 16 a, 16 b may be supplied and stored intheir respective cassettes 10 a-10 f, 11 a-11 f in an invertedorientation, such that their bottoms are uppermost and their lids arelowermost.

Also configured for movement along the main gantry 12 are an inoculatingdevice 30 and a streaking device 40. In some embodiments, both may bemounted upon a suitable carriage for movement along the main gantry inthe x direction. The inoculation device 30 may include a pipette robotsystem controlled so as to be able to access supply 32 of pipette tipsand a sample supply system 34 that includes a number of supply tubes 36,and to access a plate work position (one such position shown in FIG. 2by the letter D) for inoculation purposes. The streaking device 40 mayinclude a streaking robot system controlled so as to be able to access astreaking applicator supply 42 that, in some embodiments, includes fourapplicator supply cartridges 46 received in four corresponding cartridgeholders 44.

In some embodiments, the inoculation and streaking station C of theapparatus includes dual plate work positions D and dual rotation devices52 a, 52 b for the streaking of dual plates 16 c, 16 d as shown in FIG.2 in the dual plate work positions D, and dual plate orientationmechanisms 20 a, 20 b, the location of which is indicated in FIGS. 1 and2 by the reference numerals 50 a and 50 b. While FIG. 2 generally showsde-lidded plates 16 c, 16 d in the plate work positions D underneathdual sensors 54 a, 54 b, FIG. 1 shows dual plates 16 e, 16 f beingorientated and de-lidded by the dual orientation mechanisms 20 a, 20 b.It will of course be appreciated that such a dual configuration is notessential for an apparatus in accordance with the present invention, andthat single such stations and devices could be used. Indeed, anapparatus that includes three or four or more such stations and devicesis also envisaged.

In some embodiments, the inoculating and streaking station C is thegeneral location within the apparatus where the main functions of theapparatus occur, which location is generally centered around the platework positions D. In some embodiments, the plate work positions D aredefined by the physical location in the apparatus of the sensors 54 a,54 b, which may be rigidly mounted to respective sensor mounting frames58 a, 58 b. The apparatus may also include dual plate platforms forsupporting a plate, although the combination of FIGS. 1 and 2 shows foursuch platforms, being the dual platforms 60 a, 60 b in the positionsshown in FIG. 1, and the platforms 62 a, 62 b shown in FIG. 2. In thisrespect, these figures each show two platforms (in different positions)simply for the sake of description.

In some embodiments, each cassette 10 a, 11 a may be able to holdmultiple plates within their inner chambers. For example, cassette 10 amay hold multiple plates for the purpose of providing raw plates to theapparatus for subsequent processing, and cassette 11 a may hold multipleplates for the purpose of storing processed plates following inoculationand streaking in the apparatus. As can be seen in FIGS. 1 and 2, each ofthe cassettes 10 a, 11 a also interacts with its respective carriage 14a, 14 b to capture a plate, from below, on the respective trays 22 a, 22b due to respective internal engaging and plate release/lock means (notshown).

In some embodiments, the inoculating device 30 of the apparatus of thepresent invention may be any device that is able to obtain and hold asample, generally in a liquid form, and transfer that sample to asurface, such as the surface of a medium in a positioned plate. In someembodiments, the inoculating device 30 may be a pipette 31 mounted to arobot system (not shown) so as to be movable in the z-direction, as wellas the x- and y-directions along the main gantry 12 as mentioned above.In some embodiments, the pipette 31 may include a pressure transducerconfigured to monitor pressure and/or vacuum profiles in an internalportion of the pipette 31.

Reference is now made to FIG. 3, which is a perspective view from abovea part of the apparatus of FIG. 1 according to some embodiments of thepresent inventive subject matter. The pipette 31 may include a pipettetip 33 releasably secured thereto. In some embodiments, the pipette tip33 may include a filter and/or may be disposable. The pipette tip 33 maybe releasably secured and/or attached to the pipette 31 in a manner thatpermits easy disposal of the pipette tip 33, such as disposal afterinoculation has been affected. In some embodiments, the pipette 31 maybe programmable for aspirating and/or dispensing various sample volumesat given points in time. In some embodiments, the pipette 31 may includea positional height referencing system, such as, but not limited to, apositional height z-direction referencing system. The positional heightreferencing system may be configured to determine in three dimensionalspace the height location of the pipette tip 33 relative to the datumlevel and reference points of a platform, such as platform 60 a, 60 b,62 a, 62 b, as will be described below, and/or relative to a notionalaction line.

In some embodiments, the pipette robot system may be configured to movethe pipette 31 to access a pipette tip supply 32, which may include arack of pipette tips 33, to access the biological sample station 34,which may include a rack of sample containers such as sample tubes, toaccess the plate work position D in the inoculating and streakingstation C, and/or to access a tip waste disposal area or chute. Thepipette robot system, pipette 31, and/or pipette tip 33 may includesuitable tip securing means that is configured for the pipette tip 33 tobe secured to the pipette 31. In some embodiments, the pipette robotsystem, pipette 31, and/or pipette tip 33 may be configured to obtainand hold a sample, to dispense sample, and to dispose of a used pipettetip 33.

Referring again to FIG. 3, FIG. 3 illustrates some of the structuresused for operations that may occur in the plate work position D andillustrates a plate platform 60 a with a plate bottom 19 in acentralized and clamped position in the plate work position D. In someembodiments, the plate platform 60 a may include a plate clamping member75 in the form of three movable lugs operated by a camming device (notshown), which lugs may be configured to function as a plate centralizingmeans for centralizing the position of the plate bottom 19 on theplatform 60 a.

In some embodiments, the plate work position D may include a notionalaction line fixed in two dimensions (x,y) in a given position, togetherwith a datum level Y (e.g., the surface upon the plate platform 60 a).The action line is herein referred to as being a “notional” action linegiven that it will not be a visible action line and also will not have adetermined position in three dimensional space until the height of thesurface 70 of the medium in the plate bottom 19 is determined.

In some embodiments, the plate work position D may include a positiondetector, such as, for example, 1, 2, 3, 4, or more position detectors.The position detector may be configured and/or used to locate thesurface 70 in a plate bottom 19 and/or to detect the z-position ofmedium in the plate bottom 19. In some embodiments, the positiondetector may include a sensor 54 a. In some embodiments, the plate workposition D may include a datum level Y, which may be the uppermostsurface upon the plate platform 60 a. In some embodiments, the sensor 54a may include an ultrasonic sensing device 55 a having an ultrasonicbeam focusing element that is configured to provide a focused beam onthe surface 70 and/or within a sensing region that is central to thenotional action line. The sensor 54 a may be rigidly mounted via asensor support arm 58 a, thereby defining the general location of theplate work position D. In some embodiments, the sensor 54 a may bemounted so that it is above the plate work position D and is operativelyadjacent the plate bottom 19 held immediately therebelow in the plateplatform 60 a, the plate bottom 19 having its surface 70 open upwardly.In some embodiments, the sensor 54 a may be positioned over a platebottom 19, but may not be positioned over the starting position fordispensing a sample from a pipette tip 33.

In some embodiments, the sensor 54 a may be configured to sense thesurface 70 and/or measure the distance to the surface 70. The measureddistance may then be referenced to the datum level Y to determine asurface positional reference relative to the datum level Y in onedimension (z) for the surface 70 in the plate bottom 19. In this manner,it will be appreciated that the surface 70 can thus be located in atleast the z dimension by virtue of the determination of this surfacepositional reference. This may effectively determine the height of themedium in the plate bottom 19, at least with reference to that datumlevel Y. In this respect, and as can be seen in the figures, the datumlevel Y is a surface that forms a part of the plate platform 60 a uponwhich the plate is clamped and supported. Therefore, in someembodiments, the determination of the surface positional referenceeffectively determines the height of the medium with reference to theplate platform 60 a upon which it rests.

In some embodiments, the surface positional reference may be usedtogether with the notional action line to determine the line G in threedimensions (x,y,z) that is representative of a line across the surface70 in the positioned plate.

In some embodiments, the notional three dimensional action line that isrepresented by the line G across the surface 70 of the medium in theplate bottom 19 will be specific to the medium in that plate bottom 19only, and may be a different three dimensional action line compared tothe surface of the next plate processed in the plate work position D. Insome embodiments, the given (x, y) position of the notional action lineis, with reference to the circular plate bottom 19, located such thatthe notional action line will be a radial line for a circular plate. Insome embodiments, this means that the line G, which represents theaction line in three dimensions (x, y, z), will also be a radial line.

In some embodiments, once the position of the three dimensional actionline G for a medium in a given positioned plate in three dimensionalspace has been determined, the sample may be deposited onto the surface70 of the medium along the line G. As used herein, the reference to asample being dispensed “along” a line or there being inoculation “along”a line, is intended to include a variety of forms ofdispensing/inoculation. For example, a sample may be dispensedcontinuously along the full length of the line, or may be dispensedsemi-continuously along the line, such as may be provided by a series ofdiscrete deposits in the form of dots and/or dashes. Similarly, someembodiments include that a sample may be dispensed in a substantiallynon-linear form.

In some embodiments, the position detector may include a camera. Thecamera may be configured and/or used to detect the z-position of apipette tip 33. In some embodiments, the camera and/or sensor 54 a maybe used to determine the three dimensional action line G for a medium.

In some embodiments, a pipette pressure detector may be used todetermine the surface of medium in a positioned plate. Some embodimentsinclude using a pipette pressure detector to determine the surface ofmedium in a positioned plate after and/or during a camera and/or sensor54 a determining the three dimensional action line G for the medium. Insome embodiments, the pipette pressure detector may more accuratelydetermine the surface of the medium than the camera and/or sensor 54 a.

In some embodiments, a pipette pressure detector may be used to detectand/or determine the integrity of the pipette tip 33 attached to thepipette 31. Some embodiments include using the pipette pressure detectorto detect and/or determine that the pipette tip 33 is functioningproperly and/or is suitable for use. In some embodiments, determiningthat the pipette tip 33 is suitable for use includes determining thatthe pipette tip 33 attached to pipette 31 is suitable to aspirate anddispense a liquid. Some embodiments include using the pipette pressuredetector to detect and/or determine that the pipette tip 33 is notfunctioning properly and/or is not suitable for use. In someembodiments, the pipette pressure detector may be used to detect and/ordetermine the integrity of the pipette tip 33 prior to aspirating aliquid sample into the pipette tip 33 and/or prior to determining thesurface of medium in a positioned plate.

In some embodiments, a pipette pressure detector may be used todetermine and/or verify dispensing of a fluid from the pipette tip 33attached to the pipette 31. Some embodiments include detecting that aliquid is/was present in pipette tip 33 after a given amount of theliquid has been dispensed from the pipette tip 33 using a pipettepressure detector. Some embodiments include determining that asufficient amount of liquid is/was present in the pipette tip 33 after agiven amount of the liquid was dispensed from the pipette tip 33 using apipette pressure detector. Some embodiments include determining and/orverifying dispensing of a fluid from the pipette tip 33 attached to thepipette 31 after the pipette pressure detector has determined and/ordetected the surface of medium in a positioned plate. In someembodiments, the fluid is a liquid.

In some embodiments, a pipette pressure detector may be used to detect adroplet at the distal end of pipette tip 33 attached to the pipette 31and/or the formation of a droplet at the distal end of pipette tip 33attached to the pipette 31. Some embodiments include using the pipettepressure detector to detect a droplet and/or the formation of a dropletat the distal end of pipette tip 33 after the pipette pressure detectorhas determined the surface of medium in a positioned plate and/or afterthe pipette 31 has been positioned at a location for dispensing a liquidsample.

In some embodiments, a pipette pressure detector may be used to detect aclog in the pipette tip. In some embodiments, a pipette pressuredetector may be used to detect an empty pipette tip (i.e., a pipette tipwith no liquid present in the pipette tip).

The pipette pressure detector may include a pressure transducer and apressure data module. In some embodiments, the pressure transducer andpressure data module may be integrated into a single package. In someembodiments, the pipette pressure detector may be mounted onto thepipette 31 and/or may be integral to the pipette 31. The pressuretransducer may be in fluidic communication with an internal portion ofthe pipette 31 and/or may be built-in to the pipette 31. The pressuredata module may receive and/or transmit signals corresponding to apressure at an internal portion of the pipette 31. Some embodimentsinclude the pressure data module receiving signals from the pressuretransducer. In some embodiments, the pressure data module may convert asignal received from the pressure transducer to a different signaland/or signal format, such as, for example, from an analog signal to adigital signal. In some embodiments, the pipette pressure detector maybe used to calculate the z-position relative to the surface 70 to movethe pipette tip 33 to a desired position before the sample is dispensedfrom the pipette tip 33.

Some embodiments include using a pipette pressure detector to detectthat the surface of a medium in a given plate is at a desired positionfor dispensing a sample from the pipette tip 33. In some embodiments,the desired position may be over the starting position for dispensingthe sample from the pipette tip 33. Some embodiments include dispensinga liquid sample from the pipette tip 33 after a pipette pressuredetector has determined the position of the surface of a medium in agiven plate relative to the pipette tip 33 and/or after the pipette 31has been moved to a z-position above the surface.

In some embodiments, while the liquid sample is being dispensed from thepipette tip 33, a pipette pressure detector may detect a droplet and/orthe formation of a droplet at the distal end of pipette tip 33 attachedto pipette 31. Some embodiments include stopping dispensing of theliquid sample from pipette tip 33 upon detecting the droplet and/or theformation of the droplet at the distal end of pipette tip 33 attached topipette 31. In some embodiments, after detecting the droplet and/or theformation of the droplet at the distal end of pipette tip 33, thepipette 31 may be moved to a different position, such as, for example, adifferent position above the surface, and/or a second droplet may bedetected at the distal end of pipette tip 33 attached to pipette 31.

In some embodiments, upon dispensing a liquid sample from the pipettetip 33 onto the surface 70 of the medium, a pipette pressure detectormay be used to determine and/or verify that a remaining volume and/or asufficient amount of the liquid sample is/was present in the pipette tip33. In some embodiments, upon dispensing a liquid sample from thepipette tip 33 onto the surface 70 of the medium, the dispensed liquidmay be streaked using the streaking device 40. In some embodiments, aline of spaced apart contact surfaces of a streaking applicator maycontact at least a portion of the dispensed liquid, optionally alongline G, on the surface 70 of the medium in the plate bottom 19. In someembodiments, the streaking applicator may contact the dispensed liquidand/or medium with a given contact pressure. In some embodiments, thegiven contact pressure may be suitable for the particular streakingapplicator being used, for the composition of the liquid sample, and/orfor the particular solid growth medium being used. In some embodiments,the given contact pressure may be such that the liquid is spread whenthe platform 60 a is rotated and such that the streaking applicator doesnot undesirably gouge the surface of the medium.

As those of skill in the art will understand and appreciate, the aboveapparatus described in reference to FIGS. 1-3 is described only toprovide an example embodiment in which systems, articles of manufacture,methods, and/or computer program products of the present inventivesubject matter may be embodied. The above discussion is not intended tolimit the systems, articles of manufacture, methods, and/or computerprogram products of the present inventive subject matter to theabove-referenced apparatus. Instead, the apparatus described above inreference to FIGS. 1-3 is a non-limiting example and the systems,articles of manufacture, methods, and/or computer program products ofthe present inventive subject matter may be applied to any system,article of manufacture, method, and/or computer program product in whichpipette controls may be utilized, in which detecting a surface relativeto a pipette may be desired, and/or in which determining a pipetteposition relative to a surface may be desired.

Reference is now made to FIG. 4, which is a perspective view of apipette 80 according to some embodiments of the present inventivesubject matter. In some embodiments, the pipette 80 may include apipette tip 88 releasably attached to the pipette 80. In someembodiments, systems, articles of manufacture, methods, and/or computerprogram products of the present inventive subject matter may include apipette pressure detector 82. The pipette pressure detector 82 mayinclude a pressure transducer 84 and a pressure data module 86. In someembodiments, the pressure transducer 84 and pressure data module 86 maybe integrated into a single package. In some embodiments, the pipettepressure detector 82 may be mounted onto the pipette 80 and/or may beintegral to the pipette 80.

The pressure transducer 84 may be in fluidic communication with thepipette 80 and/or may be built-in to the pipette 80. The pressure datamodule 86 may receive and/or transmit signals corresponding to apressure at an internal portion of the pipette 80. Some embodimentsinclude the pressure data module 86 receiving signals from the pressuretransducer 84. In some embodiments, the pressure data module 86 mayconvert a signal received from the pressure transducer 84 to a differentsignal and/or signal format, such as, for example, from an analog signalto a digital signal.

The pipette pressure detector 82 may measure pressure and/or vacuumprofiles at an internal portion of a pipette. Example pipette pressuredetectors that include a pipette include, but are not limited to, thosecommercially available from Tecan under the name CAVRO® and fromHamilton Company under the name ZEUS™. In some embodiments, the pipettepressure detector 82 may use pressure data to detect and/or determinethe integrity of the pipette tip 88. In some embodiments, the pipettepressure detector 82 may use pressure data to determine that the pipettetip 88 is properly functioning and/or is suitable for use. In someembodiments, determining that the pipette tip 88 is suitable for useincludes determining that that the pipette tip 88 attached to pipette 80is suitable to aspirate and dispense a liquid. Some embodiments includeusing the pipette pressure detector to detect and/or determine that thepipette tip 88 is not functioning properly and/or is not suitable foruse. Some embodiments include aspirating a gas into the pipette tip 88while the pipette pressure detector 82 may be measuring pressure and/orvacuum profiles at an internal portion of the pipette 80 to determinewhether the pipette tip 88 attached to pipette 80 is properlyfunctioning and/or suitable for use.

In some embodiments, the pipette pressure detector 82 may use real-timepressure data to detect a surface 90 and/or to determine a position ofthe pipette 80 and/or pipette tip 88 above a surface 90.

In some embodiments, the pipette pressure detector 82 may use pressuredata to determine and/or verify dispensing of a fluid in the pipette tip88 attached to the pipette 80. In some embodiments, the fluid is aliquid. Some embodiments include determining and/or verifying dispensingof a fluid from the pipette tip 88 attached to the pipette 80 after agiven volume of fluid has been dispensed. In some embodiments, thepipette pressure detector may be used to determine and/or verify that asufficient volume of liquid is/was present in the pipette tip 88 after aportion of the liquid was dispensed.

In some embodiments, the pipette pressure detector 82 may use real-timepressure data to detect a droplet at the distal end of pipette tip 88attached to pipette 80 and/or the formation of a droplet at the distalend of pipette tip 88 attached to a pipette 80. In some embodiments, thepipette pressure detector 82 may be used to detect a clog in the pipettetip 88. In some embodiments, the pipette pressure detector 82 may beused to detect an empty pipette tip (i.e., a pipette tip with no liquidpresent in the pipette tip).

The pipette pressure detector 82 may perform and/or be utilized in oneor more operations of the methods and systems described below.

Reference is now made to FIG. 5, which is a flowchart illustratingoperations of methods according to some embodiments of the presentinventive subject matter. The methods may include measuring a pipettepressure at an internal portion of a pipette at block 100. In someembodiments, measuring a pipette pressure at an internal portion of apipette at block 100 may include generating a plurality of pipettepressure values. In some embodiments, measuring the pipette pressure atan internal portion of the pipette at block 100 is carried out using apipette pressure detector including a pipette as described above inreference to FIG. 4. The duplicate discussion of the pipette pressuredetector and pipette is omitted herein for the purposes of discussingFIG. 5.

Some embodiments include measuring pipette pressure at block 100 atgiven sampling time intervals and/or over a given time interval. Anysuitable time interval may be used to measure the pipette pressure atblock 100. In some embodiments, the total time interval over whichpipette pressure is measured at block 100 may depend on the volume of agas aspirated into a pipette tip attached to a pipette. In someembodiments, the total time interval over which pipette pressure ismeasured at block 100 may depend on the rate of aspiration of a gas intoa pipette tip attached to a pipette.

Some embodiments include measuring pipette pressure at block 100 atsampling time intervals of every 0.1 to 100 milliseconds, such as, forexample, every 1 to 50, 0.1 to 10, 1 to 10, 10 to 50, or 50 to 100milliseconds. In some embodiments, pipette pressure at block 100 ismeasured at sampling time intervals of every 0.5, 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 20, 30, 40, or more milliseconds. Thus, the total timeinterval over which pipette pressure is measured at block 100 may be thesum of each sampling time interval. The given time intervals providedherein are examples and are not intended to limit the scope of theinvention. For example, the pipette pressure may be measured at samplingtime intervals less than 0.1 milliseconds or greater than 100milliseconds.

Some embodiments include aspirating a gas into a pipette tip attached toa pipette at block 110. In some embodiments, the pipette tip includes afilter. In some embodiments, measuring a pipette pressure at an internalportion of a pipette at block 100 may include measuring pipette pressurewhile aspirating a gas into the pipette tip attached to the pipette atblock 110.

In some embodiments, gas may be aspirated into the pipette tip at block110 at a known flow rate; however, the gas may be aspirated into thepipette tip at any suitable flow rate. In some embodiments, the flowrate may depend on the characteristics of the pipette tip. Someembodiments may include tuning the flow rate based on thecharacteristics of the pipette tip. In some embodiments, gas may beaspirated into the pipette tip at a constant flow rate. Some embodimentsinclude aspirating a gas into a pipette tip at block 110 at a flow ratein a range of about 1 μL/s to about 100 mL/s, such as, for example, in arange of about 1 μL/s to about 100 μL/s, about 5 μL/s to about 40 μL/s,about 50 μL/s to about 500 μL/s, 5 μL/s to about 400 μL/s, about 100μL/s to about 300 μL/s, about 300 μL/s to about 700 μL/s, or about 1mL/s to about 100 mL/s. In some embodiments, a gas may be aspirated intoa pipette tip at block 110 at a flow rate of about 100, 200, 300, 400,500, 600, 700, 800, 900 μL/s or more. The flow rates provided herein foraspirating a gas into a pipette tip are examples and are not intended tolimit the scope of the invention. For example, the flow rate foraspirating a gas into a pipette tip may be less than 1 μL/s or greaterthan 100 mL/s.

Any suitable volume of gas may be aspirated into the pipette tip atblock 110 at any suitable rate of aspiration. In some embodiments, aknown volume of gas may be aspirated into the pipette tip at block 110.In some embodiments, the volume of gas aspirated into the pipette tip atblock 110 may be in a range of about 1 μL to about 500 mL, such as, forexample, in a range of about 5 μL to about 500 μL, about 25 μL to about150 μL, about 200 μL to about 500 μL, about 400 μL to about 1 mL, about1 mL to about 5 mL, or about 10 mL to about 500 mL. In some embodiments,the volume of gas aspirated into the pipette tip at block 110 may beabout 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350,400 μL or more. The volumes provided herein for aspirating a gas intothe pipette tip are examples and are not intended to limit the scope ofthe invention. For example, the volume of gas aspirated into a pipettetip may be less than 1 μL or greater than 500 mL.

Some embodiments include collecting pressure data at block 120. In someembodiments, pressure data may be collected while aspirating gas intothe pipette tip attached to the pipette at block 110 and/or whilemeasuring a pipette pressure at block 100. In some embodiments, thepressure data may include the plurality of pipette pressure valuesmeasured at an internal portion of the pipette, as described in regardto block 100. In some embodiments, the plurality of pipette pressurevalues may include a maximum pressure value and a minimum pressurevalue. The maximum pressure value and minimum pressure value may occurat any point in a given time interval. For example, in some embodiments,the maximum pressure value may be measured at a first point in time andthe minimum pressure value may be measured at a second point in time andthe first point in time may be before the second point in time. In someembodiments, the maximum pressure value may be measured at a first pointin time and the minimum pressure value may measured at a second point intime and the second point in time may be before the first point in time.

In some embodiments, the pressure data collected at block 120 may becollected prior to aspirating a liquid into the pipette tip. Thus, insome embodiments, only a gas may be present in the pipette tip whilepressure data is collected at block 120 and/or while a pipette pressureis being measured at block 100.

Some embodiments include estimating a pressure range value at block 130.Some embodiments include using the collected pressure data at block 120to estimate the pressure range value at block 130. In some embodiments,the pressure range value may be estimated at block 130 using twopressure values. Some embodiments include estimating the pressure rangevalue at block 130 using a maximum pressure value and a minimum pressurevalue from the plurality of pipette pressure values generated at block100. Some embodiments include estimating the difference between themaximum pressure value and the minimum pressure value to estimate thepressure range value at block 130. In some embodiments, estimating thepressure range value at block 130 includes subtracting the minimumpressure value from the maximum pressure value to obtain the pressurerange value.

Some embodiments include determining and/or detecting if the pipette tipis properly functioning at block 140. In some embodiments, determiningand/or detecting if the pipette tip is properly functioning at block 140may include comparing the pressure range value to a threshold, such as,for example, 1, 2, 3, 4, or more thresholds. Some embodiments includecomparing the pressure range value to two thresholds, such as, forexample, a lower threshold and an upper threshold. Some embodimentsinclude a threshold that may depend on and/or be tuned based on thepipette, the volume of fluid (i.e., liquid and/or gas) present in apipette tip, the rate of aspiration or dispense, and/or the fluid typeand/or properties thereof. In some embodiments, a threshold may beempirically determined.

In some embodiments, a threshold may be determined using any suitablerate of aspiration. In some embodiments, a threshold may be determinedwith a rate of aspiration in a range of about 1 μL/s to about 100 mL/s,such as, for example, in a range of about 1 μL/s to about 100 μL/s,about 5 P/s to about 40 μL/s, about 100 μL/s to about 1 mL/s, about 300μL/s to about 700 μL/s, or about 1 mL/s to about 100 mL/s. In someembodiments, a threshold may be determined with a rate of aspiration ofabout 100, 200, 300, 400, 500, 600, 700, 800, 900 μL/s or more. Therates of aspiration for determining a threshold provided herein areexamples and are not intended to limit the scope of the invention. Forexample, the rate of aspiration for determining a threshold may be lessthan 1 μL/s or greater than 100 mL/s. The rate of aspiration fordetermining a threshold may be the rate at which a gas is aspirated intoa pipette tip attached to a pipette. In some embodiments, a threshold isdetermined with a rate of aspiration that is the same as the rate atwhich a pipette aspirates gas into a pipette tip at block 110.

Some embodiments include, responsive to the pressure range value beinggreater than or equal to a lower threshold and the pressure range valuebeing less than or equal to an upper threshold, determining that thepipette tip attached to the pipette is properly functioning at block140. In some embodiments, responsive to determining that the pipette tipattached to the pipette is properly functioning at block 140, it may bedetermined that the pipette tip attached to the pipette is suitable foruse. In some embodiments, determining that the pipette tip is suitablefor use includes determining that the pipette tip attached to thepipette is suitable to aspirate and dispense a liquid. Some embodimentsinclude aspirating a liquid into the pipette tip, responsive todetermining that the pipette tip attached to the pipette is properlyfunctioning at block 140.

In some embodiments, responsive to the pressure range value being lessthan a lower threshold, it may be determined that the pipette tipattached to the pipette is not properly functioning at block 140. Insome embodiments, responsive to the pressure range value being greaterthan an upper threshold, it may be determined that the pipette tipattached to the pipette is not properly functioning at block 140. Someembodiments include removing the pipette tip from the pipette,responsive to determining that the pipette tip attached to the pipetteis not properly functioning at block 140.

Some embodiments include determining that the pipette tip is defective,clogged, and/or improperly attached to the pipette, responsive todetermining that the pipette tip attached to the pipette is not properlyfunctioning at block 140. A defective pipette tip may include a pipettetip that is clogged (partially or fully), has a manufacturing defect,does not allow sufficient air flow through, does not contain a filter,is cracked, is punctured, and/or does not form an air-tight seal withthe pipette. In some embodiments, a defective pipette tip and/or apipette tip without a filter may be detected, responsive to determiningthat the pressure range value is less than a threshold, such as, forexample, a lower threshold. In some embodiments, a defective pipette tipand/or a clogged pipette tip may be detected, responsive to determiningthat the pressure range value is greater than a threshold, such as, forexample, an upper threshold.

Reference is now made to FIG. 6, which is a flowchart illustratingoperations in systems according to some embodiments of the presentinventive subject matter. The operations in the systems may includemeasuring a pipette pressure at an internal portion of a pipette togenerate a plurality of pipette pressure values at block 210, aspiratinga gas into a pipette tip attached to the pipette at block 220,collecting pressure data at block 230, and/or estimating a pressurerange value at block 240. Each of these operations may be as describedabove in reference to FIG. 5 and duplicate discussion thereof may beomitted herein for the purpose of discussing FIG. 6.

In some embodiments, responsive to estimating a pressure range value atblock 240, it may be detected and/or determined if the pipette tip isproperly functioning at block 250. Detecting and/or determining if thepipette tip is properly functioning at block 250 may include severaladditional operations. For example, referring briefly to FIG. 7, whichillustrates additional operations for detecting and/or determining ifthe pipette tip is properly functioning at block 250, in someembodiments, the operations at block 250 may include comparing thepressure range value to a threshold. Some embodiments include comparingthe pressure range value to an upper threshold at block 280. In someembodiments, it may be determined if the pressure range value is lessthan or equal to the upper threshold at block 285. If the pressure rangevalue is greater than the upper threshold, then a system may report anon-suitable pipette tip at block 265 and/or remove the pipette tip fromthe pipette at block 275. Some embodiments include comparing thepressure range value to a lower threshold at block 290, which may beresponsive to determining that the pressure range value is less than orequal to the upper threshold at block 285. In some embodiments, it maybe determined if the pressure range value is greater than or equal tothe lower threshold at block 295. If the pressure range value is lessthan the lower threshold, then a system may report a non-suitablepipette tip at block 265 and/or remove the pipette tip from the pipetteat block 275. If the pressure range value is greater than or equal tothe lower threshold, then a system may report a suitable pipette tip atblock 262 and/or aspirate a liquid into the pipette tip at block 272.

Referring again to FIG. 6, in some embodiments, if it is determined thatthe pipette tip is not properly functioning at block 250, then a systemmay report that the pipette tip is non-suitable at block 265. In someembodiments, a report that the pipette tip is non-suitable at block 265may indicate that the pipette tip is not suitable for use and/ordefective. Some embodiments include removing the pipette tip from thepipette at block 275 responsive to determining that the pipette tip isnot properly functioning at block 250. In some embodiments, upondetermining that the pipette tip is not properly functioning at block250, then a system may stop performing the operations.

In some embodiments, if it is determined that the pipette tip isproperly functioning at block 250, then a system may report that thepipette tip is suitable at block 262. In some embodiments, a report thatthe pipette tip is suitable at block 262 may indicate that the pipettetip is suitable for use and/or not defective. Some embodiments includeaspirating a liquid into the pipette tip at block 272 responsive todetermining that the pipette tip is properly functioning at block 250.In some embodiments, upon determining that the pipette tip is properlyfunctioning at block 250, then a system may stop performing theoperations.

During one or more operations described in regard to FIG. 6, the systemmay be acting at one or more of the same and/or different operations. Insome embodiments, one or more operations may be occurring at any giventime.

Reference is now made to FIG. 8, which is a block diagram illustrating asystem 300 according to some embodiments of the present inventivesubject matter. The system may include a processor 310, a memory 312, anetwork interface 314, a pipette 330, a pipette pressure detector 340, apressure transducer 342, and pressure data module 344.

The processor 310 may be configured to execute computer program codefrom memory 312, described below as a computer readable storage medium,to perform at least some of the operations and methods described herein,and may be any conventional processor(s), including, but not limited tothe AMD Athlon™ 64, or Intel® Core™ Duo, among others. The memory 312may be coupled to the processor 310 and may include computer readableprogram code embodied therein that, when executed by the processor 310,may cause the processor 310 to receive, generate, store, and/or transmitinformation relating to an internal pressure in the pipette 330 and/orthe location of the pipette 330 (e.g., if the pipette is in contact witha surface) and/or a condition of a pipette tip (e.g., pipette tipintegrity, if a pipette tip is functioning properly, dispensing of afluid from a pipette tip, if a droplet is at the distal end of thepipette tip, if the pipette tip is clogged, and/or if the pipette tip isempty).

In some embodiments, the pipette 330 may include a pipette tip, whichmay be releasably attached to the pipette 330. The pipette 330 may be inelectronic communication with the processor 310. The pipette pressuredetector 340 may include a pressure transducer 342 and a pressure datamodule 344. In some embodiments, the pressure transducer 342 andpressure data module 344 may be integrated into a single package. Insome embodiments, the pipette pressure detector 340 may be mounted ontothe pipette 330 and/or may be integral to the pipette 340.

The pressure transducer 342 may be in fluidic communication with thepipette 330 and/or may be built-in to the pipette 330. In someembodiments, the pressure transducer 342 may measure pressure and/orvacuum profiles at an internal portion of a pipette 330. The pressuretransducer 342, pipette pressure detector 340, and/or pipette 330 maytransmit real-time pressure data to the processor 310 and/or pressuredata module 344 that may be communicatively coupled to the processor310. The real-time pressure data may be used to detect a surface and/orto determine a position of the pipette 330 and/or a pipette tip attachedto the pipette 330. The pressure data module 344 may receive and/ortransmit signals corresponding to a pressure at an internal portion ofthe pipette 330. Some embodiments include the pressure data module 344receiving signals from the pressure transducer 342. In some embodiments,the pressure data module 344 may convert a signal received from thepressure transducer 342 to a different signal and/or signal format, suchas, for example, from an analog signal to a digital signal. In someembodiments, the pressure data module 344 may transmit signals to theprocessor 310. In some embodiments, the pipette 330, pipette pressuredetector 340, pressure data module 344, and/or pressure transducer 342may be programmable. The pipette 330, pipette pressure detector 340,pressure data module 344, and/or pressure transducer 342 may performand/or be utilized in one or more operations of the methods and systemsdescribed above.

As will be appreciated by one skilled in the art, aspects of the presentdisclosure may be illustrated and described herein in any of a number ofpatentable classes or context including any new and useful process,machine, manufacture, or composition of matter, or any new and usefulimprovement thereof. Accordingly, aspects of the present disclosure maybe implemented entirely hardware, entirely software (including firmware,resident software, micro-code, etc.) or combining software and hardwareimplementation that may all generally be referred to herein as a“circuit,” “module,” “component,” or “system.” Furthermore, aspects ofthe present disclosure may take the form of a computer program productembodied in one or more computer readable media having computer readableprogram code embodied thereon.

Any combination of one or more computer readable media may be utilized.The computer readable media may be a computer readable signal medium ora computer readable storage medium. A computer readable storage mediummay be, for example, but not limited to, an electronic, magnetic,optical, electromagnetic, or semiconductor system, apparatus, or device,or any suitable combination of the foregoing. More specific examples (anon-exhaustive list) of the computer readable storage medium wouldinclude the following: a portable computer diskette, a hard disk, arandom access memory (RAM), a read-only memory (ROM), an erasableprogrammable read-only memory (EPROM or Flash memory), an appropriateoptical fiber with a repeater, a portable compact disc read-only memory(CD-ROM), an optical storage device, a magnetic storage device, or anysuitable combination of the foregoing. In the context of this document,a computer readable storage medium may be any tangible medium that cancontain, or store a program for use by or in connection with aninstruction execution system, apparatus, or device.

A computer readable signal medium may include a propagated data signalwith computer readable program code embodied therein, for example, inbaseband or as part of a carrier wave. Such a propagated signal may takeany of a variety of forms, including, but not limited to,electro-magnetic, optical, or any suitable combination thereof. Acomputer readable signal medium may be any computer readable medium thatis not a computer readable storage medium and that can communicate,propagate, or transport a program for use by or in connection with aninstruction execution system, apparatus, or device. Program codeembodied on a computer readable signal medium may be transmitted usingany appropriate medium, including but not limited to wireless, wireline,optical fiber cable, RF, etc., or any suitable combination of theforegoing.

Computer program code for carrying out operations for aspects of thepresent disclosure may be written in any combination of one or moreprogramming languages, including an object oriented programming languagesuch as Java, Scala, Smalltalk, Eiffel, JADE, Emerald, C++, C#, VB.NET,Python or the like, conventional procedural programming languages, suchas the “C” programming language, Visual Basic, Fortran 2003, Perl, COBOL2002, PHP, ABAP, dynamic programming languages such as Python, Ruby andGroovy, or other programming languages. The program code may executeentirely on the user's computer, partly on the user's computer, as astand-alone software package, partly on the user's computer and partlyon a remote computer or entirely on the remote computer or server. Inthe latter scenario, the remote computer may be connected to the user'scomputer through any type of network, including a local area network(LAN) or a wide area network (WAN), or the connection may be made to anexternal computer (for example, through the Internet using an InternetService Provider) or in a cloud computing environment or offered as aservice such as a Software as a Service (SaaS).

Aspects of the present disclosure are described herein with reference toflowchart illustrations and/or block diagrams of methods, apparatuses(systems) and computer program products according to embodiments of thedisclosure. It will be understood that each block of the flowchartillustrations and/or block diagrams, and combinations of blocks in theflowchart illustrations and/or block diagrams, can be implemented bycomputer program instructions. These computer program instructions maybe provided to a processor of a general purpose computer, specialpurpose computer, or other programmable data processing apparatus toproduce a machine, such that the instructions, which execute via theprocessor of the computer or other programmable instruction executionapparatus, create a mechanism for implementing the functions/actsspecified in the flowchart and/or block diagram block or blocks.

These computer program instructions may also be stored in a computerreadable medium that when executed can direct a computer, otherprogrammable data processing apparatus, or other devices to function ina particular manner, such that the instructions when stored in thecomputer readable medium produce an article of manufacture includinginstructions which when executed, cause a computer to implement thefunction/act specified in the flowchart and/or block diagram block orblocks. The computer program instructions may also be loaded onto acomputer, other programmable instruction execution apparatus, or otherdevices to cause a series of operational steps to be performed on thecomputer, other programmable apparatuses or other devices to produce acomputer implemented process such that the instructions which execute onthe computer or other programmable apparatus provide processes forimplementing the functions/acts specified in the flowchart and/or blockdiagram block or blocks.

Some embodiments provide that one or more of the programs may beexecuted during a portion of execution of another one of the programs inthe corresponding process operation.

The flowchart and block diagrams in the figures illustrate thearchitecture, functionality, and operation of possible implementationsof systems, methods and computer program products according to variousaspects of the present disclosure. In this regard, each block in theflowchart or block diagrams may represent a module, segment, or portionof code, which comprises one or more executable instructions forimplementing the specified logical function(s). It should also be notedthat, in some alternative implementations, the functions noted in theblock may occur out of the order noted in the figures. For example, twoblocks shown in succession may, in fact, be executed substantiallyconcurrently, or the blocks may sometimes be executed in the reverseorder, depending upon the functionality involved. It will also be notedthat each block of the block diagrams and/or flowchart illustration, andcombinations of blocks in the block diagrams and/or flowchartillustration, can be implemented by special purpose hardware-basedsystems that perform the specified functions or acts, or combinations ofspecial purpose hardware and computer instructions.

The terminology used herein is for the purpose of describing particularaspects only and is not intended to be limiting of the disclosure. Asused herein, the singular forms “a”, “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. It will be further understood that the terms “comprises”and/or “comprising,” when used in this specification, specify thepresence of stated features, integers, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, integers, steps, operations, elements,components, and/or groups thereof.

The term “about,” as used herein when referring to a measurable value,such as an amount or distance and the like, is meant to refer tovariations of up to ±20% of the specified value, such as, but notlimited to, ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified value,as well as the specified value. For example, “about X” where X is themeasurable value, is meant to include X as well as variations of ±20%,±10%, ±5%, ±1%, +0.5%, or even ±0.1% of X. A range provided herein for ameasurable value may include any other range and/or individual valuetherein.

The corresponding structures, materials, acts, and equivalents of anymeans or step plus function elements in the claims below are intended toinclude any disclosed structure, material, or act for performing thefunction in combination with other claimed elements as specificallyclaimed. The description of the present disclosure has been presentedfor purposes of illustration and description, but is not intended to beexhaustive or limited to the disclosure in the form disclosed. Manymodifications and variations will be apparent to those of ordinary skillin the art without departing from the scope and spirit of thedisclosure. The aspects of the disclosure herein were chosen anddescribed in order to best explain the principles of the disclosure andthe practical application, and to enable others of ordinary skill in theart to understand the disclosure with various modifications as aresuited to the particular use contemplated.

What is claimed is:
 1. A method comprising: collecting pressure datawhile aspirating a gas into a pipette tip attached to a pipette, thepressure data including a plurality of pressure values measured at aninternal portion of the pipette and taken over a given time interval,the plurality of pressure values including a maximum pressure value anda minimum pressure value; estimating a pressure range value between themaximum pressure value and the minimum pressure value; and responsive tothe pressure range value being greater than or equal to a lowerthreshold and the pressure range value being less than or equal to anupper threshold, determining that the pipette tip attached to thepipette is properly functioning, or responsive to the pressure rangevalue being less than a lower threshold or the pressure range valuebeing greater than an upper threshold, determining that the pipette tipattached to the pipette is not properly functioning.
 2. The method ofclaim 1, wherein collecting pressure data while aspirating the gas intothe pipette tip attached to the pipette comprises measuring pipettepressure at given time intervals.
 3. The method of claim 2, whereinaspirating the gas into the pipette tip attached to the pipette furthercomprises aspirating the gas into the pipette tip attached to thepipette over a given time interval.
 4. The method of any one of claims1-3, wherein collecting pressure data while aspirating the gas into thepipette tip attached to the pipette comprises aspirating the gas at agiven rate of aspiration.
 5. The method of claim 4, wherein the givenrate of aspiration is in a range of about 300 μL/sec to about 700μL/sec.
 6. The method of any one of claims 1-5, wherein collectingpressure data while aspirating the gas into the pipette tip attached tothe pipette comprises aspirating the gas prior to aspirating a liquidinto the pipette tip.
 7. The method of any one of claims 1-6, whereincollecting pressure data while aspirating the gas into the pipette tipattached to the pipette comprises aspirating a given volume of gas intothe pipette tip.
 8. The method of any one of claims 1-7, whereinestimating the pressure range value between the maximum pressure valueand the minimum pressure value comprises subtracting the minimumpressure value from the maximum pressure value to obtain the pressurerange value.
 9. The method of any one of claims 1-8, wherein at leastone of the upper threshold and the lower threshold is determined using agiven rate of aspiration.
 10. The method of claim 9, wherein the givenrate of aspiration is in a range of about 300 μL/sec to about 700μL/sec.
 11. The method of claim 9 or 10, wherein the given rate ofaspiration is the same as the rate of aspiration for aspirating the gasinto the pipette tip attached to the pipette.
 12. The method of any oneof claims 1-11, further comprising, responsive to the pressure rangevalue being greater than or equal to the lower threshold and thepressure range value being less than or equal to the upper threshold,determining that the pipette tip attached to the pipette is suitable foruse.
 13. The method of any one of claims 1-12, further comprising,responsive to the pressure range value being greater than or equal tothe lower threshold and the pressure range value being less than orequal to the upper threshold, aspirating a liquid into the pipette tip.14. The method of any one of claims 1-13, further comprising, responsiveto the pressure range value being less than the lower threshold or thepressure range value being greater than the upper threshold, removingthe pipette tip from the pipette.
 15. The method any one of claims 1-14,further comprising, responsive to the pressure range value being lessthan the lower threshold or the pressure range value being greater thanthe upper threshold, determining that the pipette tip is defective,clogged, and/or improperly attached to the pipette.
 16. The method ofany one of claims 1-15, further comprising detecting that the pipettetip is defective or without a filter responsive to the pressure rangevalue being less than the lower threshold.
 17. The method of any one ofclaims 1-16, further comprising detecting that the pipette tip isdefective responsive to the pressure range value being greater than theupper threshold.
 18. The method of claim 17, wherein the pipette tip isa clogged.
 19. The method of any one of claims 1-18, wherein the maximumpressure value is measured at a first point in time and the minimumpressure value is measured at a second point in time and the first pointin time is before the second point in time.
 20. The method of any one ofclaims 1-19, wherein the maximum pressure value is measured at a firstpoint in time and the minimum pressure value is measured at a secondpoint in time and the second point in time is before the first point intime.
 21. The method of any one of claims 1-20, wherein the pipette tipincludes a filter.
 22. A computer system, comprising: a processor; and amemory coupled to the processor, the memory comprising computer readableprogram code embodied therein that, when executed by the processor,causes the processor to perform any of the operations of the method ofany one of claims 1-21.
 23. The computer system of claim 22, furthercomprising an apparatus for positioning a pipette and pipetting a liquidonto a surface of a target.
 24. The computer system of claim 23, whereinthe apparatus for positioning a pipette and pipetting a liquid onto asurface includes a pipette including a pipette pressure detector.
 25. Acomputer program product comprising: a computer readable storage mediumhaving computer readable code embodied in the medium, the computer codecomprising: computer readable code to perform operations of the methodof any one of claims 1-21.